Sjgren's Syndrome (SS) is a progressive chronic autoimmune disease affecting 4 million Americans, predominately women (9:1). The disease results in the irreversible salivary and lacrimal gland tissue damage and loss of saliva and tear production, leading to significant reduction in the quality of life in these patients. This complex disease is currently poorly understood and has no effective therapy. Importantly 5% of patients with SS progress to B-cell lymphoma of the salivary glands. Diagnosis of the disease is severely hampered by the current lack of early detection and diagnostic biomarkers. Identification of biomarkers that can lead to earlier detection of SS or predict the onset of the disease is critical to improve treatment and prognosis of the patients. This is a renewal application to continue the advancement of non-invasive biomarkers for detection of patients with primary Sjgren's syndrome (pSS). In the first funding period, we have discovered and preclinically validated a panel of highly discriminatory salivary biomarkers for pSS detection. This renewal application is to advance the translational and clinical realization by performing a definitive multi-institutional validation of the salivary biomarkers for pSS to test the hypothesis that the salivary biomarker assay can augment the current clinical criteria for pSS diagnostics. The long-term goal is to develop novel diagnostics for pSS that will exert a sustained impact on clinical diagnostics for pSS. Three Specific Aims are in place to test the central hypothesis. Aim 1 is to accrual 840 SICCA patients from three Sjgren's syndrome clinical centers. Operational oversight will be provided by the Clinical Coordination & Data Management Center (CCDMC). Of note is that the study design and sample procurement will be adhering to the PRoBE principles (prospective-specimen-collection and retrospective-blinded- evaluation) which are essential to clinical validation of biomarkers. Aim 2 is to perform a multi-center validation of salivary pSS diagnosis using a panel of salivary proteomic markers that have been pre-clinically validated to have discriminatory performance for pSS detection. The markers will be further validated, detection model built and tested for its sensitivity and specificity for pSS diagnosis. Aim 3 is to perform a multi-institution validation of salivary biomarkers for pSS early detection using SICCA non- pSS patients from Aim 2 for its ability to predict pSS from baseline SICCA symptoms. This is a timely, highly relevant and impactful translational research project for the diagnosis of the second most common autoimmune disease. The outcome of the proposed project will advance the salivary biomarkers for pSS detection to the doorsteps of the FDA for a pivotal and definitive clinical trial.